U.S. patent application number 12/202599 was filed with the patent office on 2009-08-13 for pharmaceutical composition and dressing for treating skin lesion, as well as the use of cerium salt associated with a collagen matrix.
Invention is credited to Luis Eduardo da Cruz.
Application Number | 20090202434 12/202599 |
Document ID | / |
Family ID | 40939036 |
Filed Date | 2009-08-13 |
United States Patent
Application |
20090202434 |
Kind Code |
A1 |
da Cruz; Luis Eduardo |
August 13, 2009 |
Pharmaceutical Composition and Dressing for Treating Skin Lesion,
as Well as the Use of Cerium Salt Associated With a Collagen
Matrix
Abstract
The present invention refers to a pharmaceutical composition for
treating skin lesion, comprising a cerium salt on a collagen matrix
and a dermatologically acceptable carrier. The present invention
also refers to a wound dressing for treating skin lesion,
comprising the pharmaceutical composition of the present invention.
The present invention further refers to the use of a cerium salt
associated with collagen in the preparation of the pharmaceutical
composition or wound dressing according to the present invention.
The composition of the present invention can be used in topical
applications in a variety of lesion types, such as skin lesions
involving the release of toxins related to microbial proteins on
human or animal organisms, or those appointed as HSP; burns which
involve burned skin toxin formation or LPC; chronically ulcerate
skin lesions in which there is an overproduction of proteinase;
skin lesions of difficult resolution, in which control of exudate
overproduction is required; and critically infected or colonized
skin lesions.
Inventors: |
da Cruz; Luis Eduardo; (Rio
de Janeiro-RJ, BR) |
Correspondence
Address: |
ALSTON & BIRD LLP
BANK OF AMERICA PLAZA, 101 SOUTH TRYON STREET, SUITE 4000
CHARLOTTE
NC
28280-4000
US
|
Family ID: |
40939036 |
Appl. No.: |
12/202599 |
Filed: |
September 2, 2008 |
Current U.S.
Class: |
424/1.61 |
Current CPC
Class: |
A61K 47/42 20130101;
A61K 9/10 20130101; A61K 9/06 20130101; A61L 15/325 20130101; A61K
38/39 20130101; A61K 47/36 20130101; A61P 17/00 20180101; A61K
33/00 20130101; A61K 9/0014 20130101; A61K 9/19 20130101; A61K
51/1213 20130101; A61P 17/02 20180101; A61K 33/00 20130101; A61K
2300/00 20130101; A61K 38/39 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/1.61 |
International
Class: |
A61K 51/00 20060101
A61K051/00; A61P 17/02 20060101 A61P017/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 8, 2008 |
BR |
PI0800085-9 |
Claims
1. Pharmaceutical composition for treating skin lesion,
characterized by comprising a cerium salt over a collagen matrix
and a dermatologically acceptable carrier.
2. Pharmaceutical composition according to claim 1, characterized
in that the cerium salt is cerium nitrate, preferably hexahydrated
cerium nitrate.
3. Pharmaceutical composition according to claim 1, characterized
in that the collagen used is bovine collagen type I.
4. Pharmaceutical composition according to claim 1, characterized
in that the cerium salt is present in an amount ranging from 0.1%
to 5% by weight, and the collagen is present in an amount ranging
from 5% to 95% by weight, based on the total weight of the
composition.
5. Pharmaceutical composition according to claim 4, characterized
in that the cerium salt is present in an amount of 0.4% by weight
and the collagen is present in an amount of 75% by weight.
6. Pharmaceutical composition according to claim 4, characterized
in that the cerium salt is present in an amount of 2.2% by weight
and the collagen is present in an amount of 73% by weight.
7. Pharmaceutical composition according to claim 1, characterized
in that it further comprises a suspending agent.
8. Pharmaceutical composition according to claim 7, characterized
in that the suspending agent is an alginate, selected from the
group consisting of sodium alginate and calcium alginate.
9. Pharmaceutical composition according to claim 7, characterized
in that the suspending agent is present in an amount ranging from
1% to 20% by weight, based on the total weight of the
composition.
10. Pharmaceutical composition according to claim 1, characterized
in that the dermatologically acceptable carrier is water.
11. Pharmaceutical composition according to claim 1, characterized
in that it further comprises an emollient.
12. Pharmaceutical composition according to claim 11, characterized
in that the emollient is propylene glycol.
13. Pharmaceutical composition according to claim 11, characterized
in that the emollient is present in an amount ranging from 1% to
20% by weight, based on the total weight of the composition.
14. Pharmaceutical composition according to claim 1, characterized
in that the it is designed for topical application in skin lesions
involving the release, in human or animal organisms, of toxin
related to microbial proteins or those denominated as HSP, in burns
involving the formation of burned skin toxin or LPC, in chronic
ulcerated skin lesions in which there is proteinase overproduction,
and in skin lesions which were critically infected or
colonized.
15. Pharmaceutical composition according to claim 7, characterized
in that it is designed for topical application in skin lesions of
difficult resolution, in which control of exudate overproduction is
required.
16. Pharmaceutical composition according to claim 1, characterized
in that it is designed for topical application in lesions selected
from venous stasis ulcers, pressure ulcers, perforating plantar
wounds and complex surgical wounds and burns.
17. Dressing for treating skin lesion, characterized by comprising
a pharmaceutical composition as defined in claim 1.
18. Dressing according claim 17, characterized in that it is
lyophilized.
19. Dressing according to claim 17, characterized in that it is
sterilized by gamma radiation or ethylene oxide.
20. Use of cerium salt in association with collagen, characterized
in that it is for preparing a pharmaceutical composition as defined
in claim 1.
21. Method for treating skin lesion, comprising applying a
pharmaceutical composition as defined in claim 1 to the skin
lesion.
Description
BACKGROUND OF THE INVENTION
[0001] In contemporary medical practice, wound healing treatment is
based on the use of dressings, base illnesses control, debridement
of non-viable tissue, homeostasis, restoration of adequate tissue
perfusion, pressure limitation over wounded spot and infection
control.
[0002] From a historical point of view, many things have changed on
wound treatment approach until present concepts are reached. In
ancient Egypt, a wound was seen as a hole through which evil beings
coming from hell could enter a person's body. Interpreting things
like this, excrement would be applied over the lesion hoping this
could send even the worst of demons away. One of the most popular
drugs used in ancient Egypt was honey. Nowadays, its therapeutic
properties are attributed to repressing microorganism growth and,
for the fact of being hygroscopic, to attracting leukocyte and
antibodies to the wounded spot.
[0003] As far as wound dressings are concerned, the Egyptian used
to apply a technology similar to that used in the mummies embalming
process. Bandages were used to cover and keep medicine in the
desired body spots. Lynen produced in Egypt would vary in texture
from fine gauze-like fibers used nowadays to thicker fabric as the
ones used with mummies. For lesion debridement there are
descriptions of treatment with larvae, able to develop proteolytic
enzymes which degenerate the necrotic tissue and liquefy it.
[0004] Hypocrites used to recommend cleaning the wounds with warm
water, wine and vinegar and drying it. The concept that the wound
should be kept dry to provide better healing conditions persisted
until the end of the II World War. From then radical changes
regarding the basic concepts of wound healing took place. In 1958,
Odland saw that the bottom part of a blister would heal faster if
its surface was not removed. Later, using lesions of a domesticated
pig as a model, Winter showed a faster epithelium repair after
occlusion, thus revolutionizing the approach towards wound care.
Then came 1963 and Hinman et al. established the beneficial effect
of wound occlusion in human beings.
[0005] Presently, the wide range of wound healers aiming at not
only keeping the spot humid as well as other actions, such as
antimicrobial properties, are available in the market.
SUMMARY OF THE INVENTION
[0006] The present invention refers to obtaining a cell
proliferation matrix, in the form of a dressing, through tissue
bioengineering techniques, as well as its clinical applications,
which generally correspond the treatment given to lesions where
cutis integrity loss is seen, including skin mucous ulcers of
different etiologies, acting as haemostatic, topical healing,
antimicrobial and immune modulator.
[0007] The highlight of the composition of the present invention is
the association of cerium, a metal from the lanthanide series, to a
collagen matrix.
[0008] All process stages conform to Manufacturing and Control Good
Practice procedures as required by the national and international
regulatory agencies.
Theoretical Basis
Basic Wound Repair Concepts
[0009] Far beyond the linear concept triggered by growth factor
processes over inflammatory cells, repair represents interaction
amongst soluble mediators, extracellular matrix and parenchyma
cells. The extracellular matrix molecules can provide signals to
genetic expression through integrin receptors and tissue cells
interaction with the matrix can change the phenotypes as well as
cell functions.
[0010] Tissue trauma is followed by a series of events which can be
studied divided in phases (homeostasis, inflammatory, tissue
formation and wound remodeling). However, these are not mutually
exclusive allowing for temporal superposition.
[0011] Tissue aggression and the consequent burst of blood vessels
will trigger a first sequence of events that will culminate in
coagulation, or clotting. The blood clot formed is useful to keep
homeostasis, besides providing the provisory matrix for cell
migration.
[0012] Platelets adhere to interstitial connective tissue and later
aggregate to each other. In this aggregation process they release
several mediators and express clotting factors. Fibrin clot and
thrombin formed on the spot act as a nest for adhesion and
aggregation of additional platelets. Platelets fibrinogen, once
converted into fibrin by the thrombin, contributes to the fibrin
clot.
[0013] Platelets have to be considered at this moment, not only for
their important role in the making of the homeostatic cover as well
as by releasing the cytokines and growth factors exemplified in the
Platelets Derived Growth Factor (PDGF) and the Transforming Growth
Factor .alpha. and .beta. (TGF .alpha. and TGF .beta.).
[0014] Besides that, the clotting cascade itself, complement
compounds and damaged cells, generate a number of chemotactic
factors which when in association attract leukocytes to the damaged
spot. Endothelial activation by chemotactic stimulates also the
endothelial release of elastase and collagenase molecules which, in
turn, ease cellular penetration through blood vessels basal
membranes.
[0015] Leukocyte will perform the cleaning of strange bodies and
bacteria found in the system. Their persistence in the place can
extend the inflammatory stage and difficult normal repair. On the
other hand, generating chemotactic agents of the wound is generally
reduced as it is kept "clean". The neutrophil residue will
gradually be expelled with the scab or phagocytized by macrophages
or fibroblasts.
[0016] Responding to specific chemotactic factors, such as elastin,
fibronectin and collagen fragments and TGF .beta., peripheral blood
monocyte continue to be recruited by the wound where they are
activated and show a macrophage phenotype. These cells, as well as
the platelets start granulation tissue formation. Macrophages are
able to debride the tissue, digesting pathogenic organisms, tissue
debris and worn out neutrophils. Macrophage seem to perform a
fundamental role in the transition between inflammation and repair
since they secret fibroblasts growing factors needed to start and
spread the tissue remodeling in wounds.
[0017] Some hours after the aggression, keratinocytes of the
epithelium residual frames move across the wound. Important
phenotype changes are observed in the epithelium cells as
retraction of the intercellular tonofilaments, dissolution of the
intercellular desmosome in their majority, forming of peripheral
cytoplasm actin filaments and loss of firm links between dermis and
epidermis, which allows epidermis cells to display lateral
motility.
[0018] Until two days after aggression, the epithelium cells on the
edge of the wound start to migrate. Keratinocytes migrating over
the wound do not run randomly over a provisory matrix area but
really "spare" viable tissue from non-viable tissue. This migration
route is mediated by the integrins expressed by the epidermis cells
in their membranes, as for example, the keratinocytes do not
express receptors to fibrinogen, fibrin, denatured collagen or
fibronectin. Thus, migratory epidermis cells avoid clot rich in
fibrin/fibronectin and migrate over collagen type I. In the end,
keratinocytes migration brings scab discard.
[0019] Simultaneously to the re-ephitalialization, proteins from
the basal membrane appear again from the edges of the wound to the
center. Epidermis cells return to their normal phenotype, firmly
sticking to the basal membrane through hemidesmosome and to the
neodermis through collagen type VII fibrils.
[0020] After approximately four days of aggression, granulating
tissue starts to form. It got its name from the granulated
appearance seen when it is incised, due to the presence of many
newly-formed capillaries.
[0021] Angiogenesis is, in a few words, a process mediated by four
related phenomena: change in cellular phenotype, induced migration
by chemostatic, mitogen stimulation and the appropriate
extracellular matrix.
[0022] Besides vascular proliferation, fibroplasia is a marked
element in the granulation tissue. Platelets and macrophage release
a series of cytokine with proliferative and migratory activities to
fibroblasts. Later, the fibroblasts themselves will produce
cytokine and respond to them in an autocrine way.
[0023] For the fibroblasts to migrate an active proteolysis system
able to cleave a way for the migration is necessary. Various
enzymes derived from fibroblasts, together with the plasmin coming
from the serum, seem to perform this role. Those include
plasminogen activator, interstitial colagenase (matrix
metalloproteinase 1, MMP-1), gelatinase (MMP-2) and estromelisin
(MMP-3), as well as serum-derivated plasminogen.
[0024] Matrix Metalloproteinases (MMP) are a family of
extracellular proteinases responsible for regulating physiological
events, not only the remodeling of the extracellular matrix but
also influencing other cellular activities, as proliferation and
apoptosis. Their action is fine tuned through tissue inhibitors of
metalloproteinases (TIMP) and growth factors. Chemotactic factor
PDGF, for instance, stimulates the release of these enzymes by the
fibroblasts while TGF induces secretion of proteinase inhibitors,
in a display of detailed control of extracellular matrix
degradation during fibroblasts migration.
[0025] Fibroblasts, as macrophages and newly-formed blood vessels,
cleave the fibrin clot as they migrate to the wounded spot and lay
a new provisory matrix made of hyaluronan and fibronectin. The
extracellular matrix, in turn, affects the fibroblasts in their
functions of synthesis and re-shape of the matrix itself,
interaction known as dynamic reciprocity.
[0026] The following stage is marked by the production of a
collagen matrix. Summarizing, during skin repair, connective tissue
matrix dismissal happens in a sequence set of fibronectin, collagen
type III and, later, collagen type I. Production of the latter
coincides with an enhancement of wound resistance. Collagen type V
will also be enhanced during the granulation tissue development in
parallel to the vascularization of the tissue. Besides providing
structural support for new tissue resistance, collagen acts on
matrix-immersed cells, for example, changing their cellular
phenotype or working as a chemotactic element.
[0027] After the collagen matrix dismissal, the fibroblasts reshape
it and provoke wound contraction. These cells take the phenotype of
smooth muscle cells known as myofibroblasts which, through a link
to the extracellular matrix (fibronectin and collagen) and to each
other, lead to connective tissue compression and wound contraction.
Transmission of traction forces depend basically on fibroblasts
connection to collagen matrix via the integrin receptors and
crossed links among individual collagen bundles.
[0028] Transition from a granulation tissue rich in fibroblasts to
a relatively acellular matrix are followed from the cellular point
of view by fibroblast apoptosis around the tenth day of repair.
Capillae regression happens from one to two days after removal of
the angiogenesis stimuli, made through another apoptosis via.
[0029] Wound remodeling stage is marked by the extracellular matrix
remodeling and cellular differentiation or apoptosis. The
composition and extracellular matrix granulation tissue structure
is a function of time interval and distance between the edges of
the wound, that is, on larger wounds, extracellular matrix
remodeling and maturation of neo-epidermis, fibroplasias and
neovascularization start from the edge of the wound while
granulation tissue formation continues to move towards the most
central part of the lesion. This makes the extracellular matrix of
the wound edges differ from the central extracellular matrix
regarding both the qualitative and the quantitative approaches.
[0030] The first cell types to undergo apoptosis are the
endothelium cells, with a reduction in the capillae number. It will
later happen to myofibroblasts and macrophages leading to more
acellular wound repair. The extracellular matrix goes on modifying
itself along the following months and years, though slowly.
Some Influencing Factors on Skin Wound Repair
[0031] Many factors, both local and systemic, can influence the
tissue wound healing process creating unfavorable outcomes, as
hypertrophic scars or keloids or even chronic ulcers, as leg
ulcers, pressure ulcers and perforating plantar wounds.
[0032] It is well know, for example, that due to the richness of
the skin annexes, facial lesions will be repaired faster than
lesions on the feet. Low temperatures or blood flow deficiencies
can also compromise the wound repair process.
[0033] Additionally, other local factors as anoxia, abnormal pH,
necrosis, infection, hematoma and strange bodies can compromise
tissue repair. Hypoxia favors tissue migration and angiogenesis
while compromising cell proliferation, collagen synthesis and
resistance against bacteria.
[0034] On wounds where the repair evolves naturally there is a
balance between the MMPs and TIMPs expressions; on the other hand,
on chronic ulcerate lesions, as inferior ulcers, there is growing
evidence of a local proteolysis increase. Hart et al. highlight
that the destructive action of these high levels of proteases can
be a compromising factor to wound healing in chronic ulcers. The
excessive activity of proteinase seem to deprive wounds of having
an initial matrix that could work as a lead to cell migration and
framework for matrix storage and growth factor keeping, key
elements involved in orchestrating the new tissue making process. A
high proteases activity level can even cause damage to cellular
surface proteins as growth factors receptors and integrins
receptors, damage enough to create an impact on the activity of all
cells engaged on the tissue repair process.
[0035] Infection is an important cause of repair delay. Although
almost all skin wounds are contaminated by the existing flora,
pathogenic organisms need to represent a value over the 100.000
bacteria per gram of tissue mark if the clinic infection is to
happen. If bacterial colonization is evaluated as critical, it can
provoke a longer than desired inflammatory stage and thus
compromise repair and if so, should be treated with topical
antiseptics.
[0036] In optimized wound repair timelines, one should also drain
any hematoma and avoid drugs that ease their formation, as
anti-clotting and anti-platelet agents. Strange bodies represent a
fitting place for bacteria adherence, reducing oxygen tension and
wound pH, so they must be removed.
[0037] Regarding systemic factors, both the nutritional features
and the quality of life (smoking, alcohol abuse), the use of some
drugs (as corticosteroids) or systemic diseases, as diabetes
mellitus, can compromise the progress of wound repair processes.
Old-age patients show a reduction in their protein synthesis,
delayed lymphocitary migration and a persisting inflammatory stage,
besides being subject to malnutrition risks, concomitant diseases
and use of medicament.
[0038] The fluid seen in chronic ulcers, as pressure ulcers, venous
stasis ulcers and diabetic foot, all inhibit cellular
proliferation, mainly of fibroblasts. This fluid is rich in tumor
necrosis factor (TNF .alpha.). It is supposed that substances able
to reduce the level of this cytokine, such as cerium nitrate, can
positively module chronic ulcers repair.
[0039] Lastly, apart from what was thought in the past, there is
presently clear evidence that a dried wound will not heal as well
as one treated on a humid environment. The benefits of a humid
environment include the promotion of re-ephitalialization, dermis
repair and angiogenesis. Topical medicine and occlusive dressings
provide a humid environment that helps in the wound repair.
Collagen
[0040] Collagens are glycoprotein of extracellular matrix composed
of three chains and forming triple helix along part of their
primary sequence. There are 18 types of appointed collagen, from I
to XVIII according to the date they were discovered.
[0041] The majority of the studies made over the content of
collagen found in repairing wounds and artificially induced
granulation tissue (implanted sponges) has examined collagen types
I and III, since these two collagen have been characterized for
some time and their supramolecular structures are clearly
established.
[0042] Hard helical collagen macromolecules aggregated in fibril
sheaves gradually give repair tissue an enhancement in tensile
strength and firmness. Besides working to support structure for the
new tissue resistance, collagen can have a profound effect on
matrix-immersed cells. Peptides derived from collagen, for
instance, work as chemotactic for in vitro fibroblasts and can have
a similar in vivo effect. Furthermore, intact collagen can change
the phenotype and function of a variety of different. These effects
can be partially measured through the activation of integrin
receptors for collagen .alpha.1.beta.1 and .alpha.2.beta.1.
[0043] Collagen re-shape during the transition period of
granulation tissue for a mature repair is dependent on both the
continuous synthesis of the collagen as well as on the collagen
catabolism. Collagen degradation on wound is controlled by a
variety of collagenase enzymes of granulocytes, macrophages,
epidermis cells and fibroblasts. These activities are controlled by
various similar inhibitors known as tissue inhibitors of
metalloproteinases (TIMP), which are then regulated during
development and seemingly during wound repair. Cytokines as the TGF
.beta., PDGF and IL-1 and the extracellular matrix itself can
perform an important role in modulating collagenase and TIMP in
vivo expression.
[0044] Wounds gain only about 20 percent of their final Power on
the third week, during which fibrillar collagen accumulated
relatively fast and was systematically re-shaped by wound
contraction driven by the myfibroblasts. In fact, gradual gain in
tension power is less related to new collagen dismissal than to
additional collagen re-shape, thicker formation of collagen sheaves
and a change to cross molecule links. So, the wounded tissue does
not have the same resistance than the non-wounded skin. In its
maximum resistance output, a scar will have the maximum of 70
percent of the power of the intact skin.
[0045] Hart et al. showed that dressings made from collagen are
capable of absorbing a wide range of factors present in chronic
ulcers and able of making the healing process more difficult, as
proteases, free radicals, and ferric ions. Besides that, they have
also reported dressings made from collagen are able to attach to
one another and protect growth factors like PDGF, maintaining their
biological activity and making the environment even more favorable
to skin repair.
[0046] In ulcers, applied collagen will work as haemostatic,
chemotactic and as a matrix for cell migration. Further, it can get
linked and inactivate matrix metalloproteinase present in excess in
chronic ulcers, and in these conditions, harmful to the tissue
repair process. On the other hand, growth factors will be kept in
contact with the wound bed and protected from action of proteases.
The fact it is bio-compatible is yet another positive point
favoring the use of the collagen matrix.
Cerium Nitrate
[0047] The metal cerium holds powerful anti-microbial action and
presents low toxicity towards mammal cells. Burkes & McCleskey
have shown that cerium salts are toxic in vitro to bacteria and
fungi. In 39 bacteria species studied, cerium nitrate inhibited the
growth in concentrations in the order of 0.0004 M. Although the
biochemical levels in which cerium exerts its bacteriostatic
effects are still unknown, the possibilities are many. A change in
bacteria cell walls negative charge has been reported, leading to
the migration and agglutination of microorganisms. Lanthanide also
responds to nucleic acid and makes insoluble complexes.
[0048] It has been shown that human burns when in contact with
cerium salts for weeks were less frequently colonized by Gram
negative bacteria. Fox et al. (1977) reported the association of
cerium nitrate and silver sulfadiazine resulting in an increase in
clinic efficacy for patients with severe burns. Observations have
confirmed topical cerium reverted T lymphocyte failure common to
burns. This beneficial effect is related to cerium link to a
lipoprotein complex (LPC) existent on burn lesion.
[0049] Tumor necrosis factor (TNF-.alpha.) is the most powerful
inflammatory cytokine. It is well known that excessive release of
cytokines has a harmful action over the immunological function.
Deveci et al. demonstrated that treating lesions to cerium nitrate
(CN) resulted in an increase of interleucin-6 and in a reduction of
TNF-.alpha., limiting the extent of the inflammatory reaction.
There are then evidences that this metal is useful in treating
chronic lesions, by the unorganized presence of mediators of the
inflammatory response, like interleukins and TNF14, 31.
[0050] Within the context of chronic ulcers and burns, the
advantages of adding cerium nitrate to a dressing are:
antimicrobial action, immuno modulating action, anti-inflammatory
action by reducing levels of TNF-.alpha..
DESCRIPTION OF THE INVENTION
[0051] The invention refers to the production of cellular
proliferation matrix, in the form of a dressing, obtained through
bioengineering techniques, comprising bovine collagen in
association with a cerium salt and, as an option, an alginate with
haemostatic, wound repairing, antimicrobial, immunomodulating
properties, able to absorb exudates excess, keeping the environment
humid, though at the same time preventing maceration of the lesion
and whose therapeutic action is related to treating the infection
and wound colonization, as a result of its wide spectrum of
antimicrobial action.
[0052] Its wound healing properties come from collagen acting as a
structural support and facilitator of cell migration besides
performing a protective role for the newly-produced collagen in a
collagenase-rich environment, common in chronic ulcers.
Additionally, the presence of toxins on the burn-affected skin,
like LPC, and that of inflammatory cytokines largely produced in
the environment of chronic ulcers, as Tumor Necrosis Factor-Alfa,
can perpetuate the inflammatory reaction, that can be modulated by
the presence of the metal cerium. Conjugating together wound
repairing, anti-microbial and immunomodulator actions, will make
the dressing of the present invention an efficient therapeutic
agent for burns and wounds of different etiologies, as: venous
stases ulcers, pressure ulcers, plantar skin ulcers, complicated
surgical wounds and burns.
[0053] The composition of the present invention has the appearance
of an opaque gel and can be formulated as a dressing of varying
sizes. The technique used for dressing preparation in the present
invention consists of dissolving the cerium salt, particularly
cerium nitrate, in a dermatologically acceptable carrier,
preferably water, adding the solution of cerium salt to collagen
and homogenize. In a preferred form, the mixture obtained must be
homogenized to an alginate dispersion into an emollient, preferably
propylene glycol, until it becomes a uniform mass. Then it is time
to bottle it in specific forms according to desired formats and,
subsequent freeze drying (lyophilization). After freeze drying
(lyophilization) the product will have a spongy aspect, similar to
fiber frame. The end product can then be sterilized through gamma
radiation or ethylene oxide.
DETAILED DESCRIPTION OF THE INVENTION
[0054] The present invention refers to a pharmaceutical composition
for treating skin lesion comprising a cerium salt over a collagen
matrix and a dermatologically acceptable carrier.
[0055] Preferably the cerium salt used is the cerium nitrate, in
particular hexahydrated cerium nitrate, and the collagen used is
bovine collagen type I.
[0056] Cerium salt can be present in the composition in amounts
ranging from 0.1% to 5% by weight and the collagen varying from 5%
to 95% by weight, based on the total weight of the composition.
Preferably, cerium salt is present in amounts from 0.4% to 2.2% by
weight and the collagen is present in amounts from 73% to 75% by
weight, based on the total weight of the composition.
[0057] In a preferred embodiment of the invention, cerium salt is
present in an amount of 75% by weight and the colagen is present in
an amount of 0.4% by weight, based on the total weight of the
composition.
[0058] In another preferred embodiment of the invention, cerium
salt is present in an amount representing 73% by weight and
collagen responds for 2.2% by weight, based on the total weight of
the composition.
[0059] The composition of the present invention can also include a
suspending agent. Preferably, this suspending agent will be an
alginate, which can be chosen from sodium alginate and calcium
alginate. The suspension agent can be present in amounts ranging
from 1% to 20% by weight, based on the total weight of the
composition, and its amount will preferably range from 5% a 15% by
weight, particularly in an amount of 10% by weight.
[0060] The dermatologically acceptable carrier used in the
composition of the present invention is preferably water.
[0061] The composition of the present invention can also be
comprised of an emollient, preferably propylene glycol, which can
be present in amounts varying from 1% to 20% by weight, based on
the total weight of the composition, preferably in amounts ranging
from 5% to 15% by weight, particularly in an amount of 10% by
weight.
[0062] The composition of the present invention can be used in
topical applications in a variety of lesion types, such as skin
lesions involving the release of toxins related to microbial
proteins on human or animal organisms, or those appointed as HSP;
burns which involve burned skin toxin formation or LPC; chronically
ulcerate skin lesions in which there is an overproduction of
proteinase; skin lesions of difficult resolution, in which control
of exudate overproduction is required; and critically infected or
colonized skin lesions.
[0063] The present invention is also related to a dressing for
treating skin lesion comprising the pharmaceutical composition of
the present invention. Preferably, it is a lyophilized dressing and
can be sterilized by gamma rays or ethylene oxide.
[0064] The present invention also refers to a cerium salt
associated with a collagen in the preparation of a pharmaceutical
composition or dressing according to the present invention.
[0065] In addition, the present invention also refers to a method
for treating skin lesion by applying a pharmaceutical composition
or a dressing as disclosed herein.
Features of the Invention
[0066] Association of a substance promoting repair (collagen) to
anti-microbial and immunomodulator substances (cerium salt,
particularly cerium nitrate) in the form of a dressing. [0067]
Development of dressing formulation and production processes, using
the tissue engineering technique, which will work as a cell
proliferation matrix with hemostastatic, anti-microbial and
immunomodulating properties, composed especially of collagen in
association to a cerium salt, particularly cerium nitrate and
optionally an (sodium or calcium) alginate. Advantages of the
product in relation to the state of the technique.
[0068] The described dressing promotes tissue repair through the
biological effects of collagen, which works as a structural support
and facilitator for cell migration besides having a protective role
of the newly-produced collagen in a collagenase-rich environment,
common to chronic ulcers, in association with cerium salt
antimicrobial and immunomodulating effects, described by severely
burned patients and those suffering with chronic ulcers.
[0069] Preferably, a suspending agent should be used in the
composition of the present invention. Best choice for the present
invention suspending agent is an alginate. Particularly sodium or
calcium alginate should be used. The presence of the (sodium or
calcium) alginate works as a lesion humidity control mechanism,
absorbing exudates excess, which avoids wound edge maceration and
keeps the ideal humidity level in the wound.
[0070] The present invention dressing does not adhere to the bed,
thus avoiding trauma during changes in the newly-formed tissue, and
can be trimmed to the shape of the wound. In its range of
applications there are indications for difficult resolution wounds,
even those with critical bacteria colonization levels or those over
which infection develops, through the work of the cerium metal
antimicrobial action. Its clinical applications are, therefore:
Burns, leg ulcers (venous stasis ulcers) artery and mixed ulcers,
diabetic foot, pressure ulcers, surgical and trauma wounds.
[0071] Regarding the hydrocolloid dressings, the proposed product
has the advantages of acting over protein and microbial toxins or
HSP proteins and present antimicrobial, haemostatic properties,
besides modulating lesions with proteases excess.
[0072] There are other collagen-containing dressings in the market,
such as Fibracol.RTM., Fibracol Plus.RTM., Promogran.RTM., amongst
others. Such dressings have the limitation of not having an
antimicrobial action, which can be critical in some clinical
instances, as it is the case of chronic ulcers. These kind of
ulcers are generally colonized by bacteria and it is known that
critical levels of colonization are harmful to wound healing
processes, even when devoid of infection. Products using only
collagen, therefore, would have their application range widely
limited to specific wound repair stages when no signal of infection
or critical bacteria colonization could be detected and they should
be replaced whenever these situations happen.
[0073] The present invention dressing offers cerium salt,
particularly cerium nitrate, and its antimicrobial activity, as an
association to collagen. The same substance is present in another
antimicrobial and wound repair cream available in the market,
Dermacerium.RTM.. Cerium salt, particularly cerium nitrate, brings
additional property of immunomodulation, as already mentioned.
[0074] The choice made for cerium salt, particularly cerium
nitrate, as an antimicrobial element present in the dressing was
due, not only to its immunomodulating properties, as well as for
the fact that there have been no relevant reports to date of the
development of microbial resistance, even after years of use.
Presentation in the form of dressings is more interesting than in
the form of cream in the sense that it won't need so frequent
replacements, and so will reduce costs and special personnel.
[0075] The market for dressings for different lesions is described
in Table 1 below:
TABLE-US-00001 TABLE 1 World Compound Incidences (in Healing Time
annual growth Type of Lesion million) (days) rate (CAGR) Surgical
Lesions 97 14 3.1% Trauma Lesions 1.6 28 1.4% Lacerations 19.4 14
1.0% Burns 9.7 21 1.0% Chronic Lesions 26.3 -- 7.4% Carcinomas 0.6
14 3.0% Melanomas 0.2 14 3.0% Complex Skin Cancers 0.2 28 3.0%
Source: MedMarket Diligence, LLC
Best Mode for Carrying Out the Invention
[0076] Detailed illustrative embodiments of the invention disclosed
herein exemplify the invention and are currently considered to be
the best embodiments for such purposes. They are provided by way of
illustration and not limitation of the invention. Various
modifications thereof will occur to those skilled in the art, and
such modifications are within the scope of the claims which define
the present invention.
[0077] The best modes for carrying out the present invention
are:
[0078] a) A pharmaceutical composition for treating skin lesion
comprising from 0.4% to 2.2% by weight of a cerium salt over a
matrix comprising from 73% to 75% by weight of bovine collagen type
I and water, said composition optionally comprising calcium or
sodium alginate as a suspending agent and 10% by weight of
propylene glycol as emollient.
[0079] b) A dressing for treating skin lesion comprising a
pharmaceutical composition comprising from 0.4% to 2.2% by weight
of a cerium salt over a matrix comprising from 73% to 75% by weight
of bovine collagen type I and water, said composition optionally
comprising calcium or sodium alginate as a suspending agent and 10%
by weight of propylene glycol as emollient.
[0080] c) A method for treating skin lesion comprising the step of
applying a pharmaceutical composition or a dressing as disclosed
above on said skin lesion.
Sample Formulations
Formulation 1:
TABLE-US-00002 [0081] Preferred Special Concentration Concentration
Raw material (% w/w) (% w/w) Properties Bovine Collagen 5 to 95%
75% Hemostatic, Type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 0.4% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
Formulation 2:
TABLE-US-00003 [0082] Preferred Special Concentration Concentration
Raw material (% w/w) (% w/w) Properties Bovine Collagen 5% to 95%
73% Hemostatic, Type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 2.2% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
Formulation 3:
TABLE-US-00004 [0083] Preferred Special Concentration Concentration
Raw material (% w/w) (% w/w) Properties Bovine Collagen 5 to 95%
75% Hemostatic, Type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 0.4% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Sodium
alginate 1% to 20% 10% Suspending agent, exudate absorber Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
Formulation 4:
TABLE-US-00005 [0084] Preferred Special Concentration Concentration
Raw material (% w/w) (% w/w) Properties Bovine Collagen 5% to 95%
75% Hemostatic, Type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 0.4% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Calcium
alginate 1% to 20% 10% Suspending agent, exudate absorber Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
Formulation 5:
TABLE-US-00006 [0085] Preferred Special Concentration concentration
Raw material (% w/w) (% w/w) Properties Bovine collagen 5 to 95%
73% Hemostatic, type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 2.2% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Sodium
alginate 1% to 20% 10% Suspending agent, exudate absorber Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
Formulation 6:
TABLE-US-00007 [0086] Preferred Special Concentration concentration
Raw material (% w/w) (% w/w) Properties Bovine collagen 5% to 95%
73% Hemostatic, type I chemotactic and matrix for cell migration
Cerium Nitrate 0.1% to 5% 2.2% Antimicrobian, immunomodulador,
anti-inflammatory (reduction of TNF-.alpha. levels). Calcium
alginate 1% to 20% 10% Suspending agent, exudate absorber Propylene
Glycol 1% to 20% 10% Emollient Water q.s.p. 100% Carrier
[0087] The examples shown above are preferred and illustrative
variations of the present invention composition and should not be
interpreted as limitations to it. In this regard, it should be
understood that the scope of the present invention comprehends the
possibility of other variations to the composition, these being
limited only by the context of the claims here incorporated, with
possible equivalents hereon included.
Bacteriostatic Evaluation Test
[0088] Bacteriostatic evaluation of the present invention product
was performed according to the "Manual de Saneantes do Instituto
Nacional de Controle de Qualidade em Sa de--Item 8-B: Metodos para
Avaliacao da Atividade Inibitoria de Preparacoes Liquida, Cremosa e
Solida--Metodo da Placa de gar"--January 1992, for the following
microorganisms: Staphylococcus aureus ATCC 6538 and Salmonella
choleraesuis ATCC 10708. Test result proved the bacteriostatic
action of the product after a clear inhibition zone formed around
the sample.
* * * * *